Hard capsule

ABSTRACT

The present invention is directed to a hard capsule filled with a solution containing an active ingredient, characterized in that the solution contains an inorganic chloride and has a water content (w) of 10&lt;w≦80% and a water activity (a) of 0.50≦a≦0.90, and that the capsule is made of a base material containing a cellulose derivative. According to the present invention, a solution having high water content can be encapsulated, with its solution form being maintained. Thus, the present invention enables provision of a product which does not impair properties and stability of a drug or a similar substance, and does not impair sensation upon intake or eating sensation.

TECHNICAL FIELD

The present invention relates to hard capsules useful as medical drugs,quasi-drugs, cosmetics, and foods, and more particularly to hardcapsules which are able to hold ingredients of high water content.

BACKGROUND ART

In medical and food applications, capsules have conventionally beenemployed as the appliances required for improving compliance upon use.In particular, hard capsules can be produced easily and therefore havebeen widely used for containing solid substances such as powder,granules, and fine granules, or oily substances.

Hard capsules typically make use of gelatin as a shell-forming material,and therefore, they have high solubility in water. When an activecomponent of high water content is directly charged in such a hardcapsule, the internal solution renders the gelatin shells dissolved ormoistened, permitting deformation of the shape of the capsules orleakage of the internal solution. As a result, the capsule has no valueas a marketable product. Therefore, when the material to be encapsulatedcontains an aqueous solution, conventional approaches to avoid theeffect of the water include addition of an excipient and solidificationthrough, for example, concentration or drying, performed beforeencapsulation. In the case where a material is desired to be charged incapsules with its liquidity being maintained, the material is suspendedor emulsified in an oily substance before being encapsulated.Alternatively, glycerol is added to the material and the resultantmixture is heated to evaporate the water so as to attain a water contentof 10% or less, followed by filling in capsules formed of a cellulosederivative (e.g., Patent Document 1).

However, when subjected to a solidification process with heat, an animalor plant extract, such as a medicinal herb extract, is prone to changeits intrinsic taste, odor, properties, and components. Moreover, whenhard capsules containing such an extract are produced by means ofsolidification through addition of an excipient, formation of suspensionor emulsification in an oily base, or reduction of a water content to10% or less (which is attained by adding glycerol in an amount as highas 20% to 80% on a final product basis, followed by heating), drawbackssuch as limitation being imposed on the amount of the active ingredientincorporated and a rise in production cost are unavoidable.

Meanwhile, soft capsules have been known to be able to contain liquidingredients. In the case of soft capsules, encapsulation of ingredientsof high water content, such as medicinal herb extracts, requires certaintechniques. For example, a moisture-containing plant extract or asimilar substance needs to be emulsified with a fatty acid glyceride togive a soft capsule (e.g., Patent Document 2), or, a gelatin sheet and apolysaccharide sheet need to be formed into a soft capsule having alayered structure in order to impart water resistance to a gelatinshell. (e.g., Patent Document 3). As a result, its production steps andproduction conditions get intricate, raising concern about increasedcost.

Therefore, there has been a need for a technique capable of, throughsimple production steps and at low cost, encapsulating an aqueousextract of medicinal herbs, an aqueous extract of animal or plantorigin, or a similar substance without permitting volatilization ordegradation of active ingredients, while the resultant capsule productsdo not impair sensation (taste, odor, etc.) upon intake.

Patent Document 1: U.S. Pat. No. 6,238,696

Patent Document 2: JP-A-52-35178

Patent Document 3: JP-A-63-164858

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a hard capsule filledwith a solution containing an active ingredient of high water content,such as an aqueous extract of medicinal herbs, an aqueous extract ofanimal or plant origin, or a similar substance, without impairing itsquality for a prolonged period of time.

In view of the foregoing, the present inventors have performed extensivestudies on the relation between properties of a base material of acapsule and water content of the solution to be encapsulated, and havefound that, through use in combination of a solution containing anactive ingredient and an inorganic chloride and having a water contentand a water activity each falling within a specific range and capsulesformed of a specific capsule base material, the solution can beencapsulated in the capsules with its solution form being maintained,whereby hard capsules filled with the solution which can be stored for along period of time can be prepared. The present invention has beenaccomplished on the basis of this finding.

Accordingly, the present invention provides a hard capsule filled with asolution containing an active ingredient, characterized in that thesolution contains an inorganic chloride and has a water content (w) of10<w≦80% and a water activity (a) of 0.50≦a≦0.90, and the capsule ismade of a base material containing a cellulose derivative.

According to the present invention, a solution containing an activeingredient and having high water content can be encapsulated without useof an excipient or a similar additive, with its solution form beingmaintained. The capsules containing the solution are stable and do notundergo wetting or deformation during a long-term storage. Accordingly,the present invention enables provision of a product which does notimpair properties and stability of a drug or a similar substance in thepresence of a solution having a high water content, and does not impairsensation upon intake or texture. The hard capsules of the presentinvention can be produced efficiently, because their contents can bereadily charged into the capsule shells owing to their liquid nature andthe volume of the contents are easily adjusted.

BEST MODE FOR CARRYING OUT THE INVENTION

The solution to be enclosed in the hard capsule of the present invention(hereinafter referred to as “internal solution”) is a solutioncontaining an inorganic chloride in addition to an active ingredient,and has a water content (w) of 10<w≦80% and a water activity (a) of0.50≦a≦0.90.

As used herein, the term “water activity (a)” of a water-containingmedium is defined as the ratio P/P₀, of water vapor pressure of themedium (P) to vapor pressure of pure water (P₀) under the conditionswhere both pressures are measured at the same temperature. The wateractivity is a parameter representing activity of water in a medium.

No particular limitation is imposed on the internal solution so long asthe solution has a water content (w) falling within a range of 10<w≦80%and a water activity (a) falling within a range of 0.50≦a≦0.90. Theinternal solution is not limited to aqueous solutions. When a portion ofactive ingredients is difficult to dissolve in water, a suspension or anO/W-type emulsion may be employed.

No particular limitation is imposed on the active ingredients of theinternal solution, and they may be compounds or compositions ofarbitrary substances, such as medical drugs, natural materials, foods,herbal medicines in the form of extracts, plant extracts, and fermentedmatter.

Specifically, examples of the active ingredients include aqueousextracts prepared by subjecting medicinal herbs, animal- orplant-originating substances, fermented matter, or like substances toextraction with water, hydrated alcohol, or a similar solvent. Specificexamples falling under this category include herbal medicines in theform of aqueous extracts, such as ginseng, garlic, Acanthopanaxsenticosus Harms, Angelica sinensis, Rehmammia glutinosa, Citrusreticulata, Cuscuta chinensis, Schizandra chinensis, and Ophiopogonjaponicus; aqueous extracts of herbal mixtures employed in kanpo(traditional Chinese medicine), available under the names of kakkon-to,bakumonto-to, sho seiryu-to, orengedoku-to, shimotsu-to, and shakuyakukanzo-to; aqueous extracts of animal- or plant-origin, prepared from,for example, blueberries, green tea leaves, herbs, mushrooms, andmamushi (Japanese copperhead); and aqueous extracts of fermented matterproduced by fermenting grains, plants, or marine products withmicroorganisms such as koji mold, beni koji mold, lactic acid bacteria,acetic acid bacteria, Bacillus natto, and yeast. Other examples of theinternal solution include solutions in water of aqueous vitamins such asvitamin B1, vitamin B2, niacin, vitamin B6, vitamin B12, vitamin C,pantothenic acid, biotin, folic acid, and pantothenyl alcohol; solutionsin water of dextromethorphan hydrobromide, acetaminophen,chlorphenylamine maleate, potassium guaiacolsulfonate, caffeine,dihydrocodeine phosphate, methylephedrine hydrochloride, andwater-soluble azulene; and suspensions of aldioxa, magnesium hydroxide,sucralfate, magnesium aluminometasilicate, and synthetic hydrotalcite.In particular, herbal medicines in the form of aqueous extracts, aqueousextracts of animal- or plant-origin, and aqueous extracts of fermentedmatter are preferred, because they are stable as aqueous solutions, andthey can be handled in their solution form during the capsuleformulation process.

According to the present invention, an inorganic chloride isincorporated into the internal solution. By virtue of co-presence of theinorganic chloride, a solution of high water content can be encapsulatedin the capsules with its solution form being maintained, wherebycapsules filled with a solution which can be stored for a long period oftime can be produced.

Examples of the inorganic chloride include inorganic chlorides whichreleases chloride ions in a solution, such as potassium chloride, sodiumchloride, calcium chloride, magnesium chloride, ammonium chloride, andbarium chloride. Among them, sodium chloride, calcium chloride, andmagnesium chloride are preferred. These inorganic chlorides may be usedsingly or in combination of two or more species.

The inorganic chloride is incorporated into an internal solution in anamount of 0.01 to 0.45 g/mL, preferably 0.20 to 0.45 g/mL, in order toenhance stability of capsules.

If needed, the internal solution may contain other ingredients, such assweetener, acidulant, stabilizer, thickener, pH regulator, preservative,colorant, and flavoring agent, which are generally used in theproduction of foods and drugs.

Here, examples of the sweetening agent include sugars such as sucrose,lactose, fructose, and glucose; sugar alcohols such as sorbitol,erythritol, mannitol, xylitol, and trehalose; glycyrrhizin; aspartame;and stevia. These sweetening agents may be used singly or in combinationof two or more species.

As the acidulant, those commonly employed in the production of drugs andfoods may be used. Examples of acidulants include citric acid, malicacid, succinic acid, fumaric acid, tartaric acid, and lactic acid. Theseacidulants may be used singly or in combination of two or more species.

Examples of the stabilizer include antioxidants such as ascorbic acid,erythorbic acid, and sodium pyrosulfite; dispersants such as sodiumpyrophosphate, sodium polyphosphate, and sodium metaphosphate;surfactants such as sucrose fatty acid esters, polyoxyethylenehydrogenated castor oil, and polyoxyethylene polyoxypropylene glycol;cyclodextrins such as cyclodextrin, glucosyl-cyclodextrin,maltosyl-cyclodextrin, and hydroxypropyl-cyclodextrin. These stabilizersmay be used singly or in combination of two or more species.

Examples of the thickener include polymers such as dextrin, sodiumalginate, propylene glycol alginate, tragacanth powder, xanthan gum,carrageenan, agar, pectin, carboxymethylcellulose-Na, hydroxypropylcellolose, polyvinyl alcohol, and polyvinyl pyrrolidone. Thesethickeners may be used singly or in combination of two or more species.

As for the pH regulator, those generally employed in the shape-impartingart may be used. Examples thereof include organic and inorganic acidssuch as hydrochloric acid, acetic acid, phosphoric acid, citric acid,malic acid, succinic acid, fumaric acid, tartaric acid, lactic acid, andsalts of any of these acids, alkalis such as sodium hydroxide, potassiumhydroxide, sodium hydrogencarbonate, and sodium dihydrogenphosphate.These pH regulators may be used singly or in combination with one ormore of them.

Examples of the preservative include benzoic acids, sorbic acids,p-hydroxybenzoic esters, and salicylic acids. These preservatives may beused singly or in combination of two or more species.

Examples of the colorant include caramel, sodium copper chlorophyllin,riboflavin sodium phosphate, indigocarmine, Brilliant Blue, tartrazine,sunset yellow, new coccine, amaranth, and erythrosine. These colorantsmay be used singly or in combination of two or more species.

As for the flavoring agents, those generally employed for themanufacture of drugs and foods may be used, including, for example,fennel oil, orange oil, cinnamon oil, orange peel oil, mentha oil,vanillin, and eucalyptus oil. In addition to these, there may beemployed natural-originating flavors and compounded flavors which areproduced using any of these materials as raw material.

The foregoing internal solutions may be adjusted so as to be 10<w≦80% inthe water content (w) and 0.50≦a≦0.90 in the water activity (a),respectively. Preferably, the water content is 10<w≦75% and the wateractivity is 0.50≦a≦0.80, with 10<w≦70% and 0.50≦a≦0.75 being morepreferred.

When the water content of the internal solution exceeds 80% or the wateractivity exceeds 0.90, stability of the capsules holding the solution isreduced, which is not preferred. Meanwhile, a water content less than10% or a water activity below 0.50 should also be avoided, because undersuch conditions, the viscosity of the internal solution extremelyincreases, thereby failing to attain smooth flow of the solution, sothat it becomes difficult to fill the shells during production ofcapsules.

No particular limitation is imposed on the methods of adjusting watercontent (w) or water activity (a). For example, either of thefollowing 1) or 2) may be performed: 1) Soluble solid matter is causedto dissolve in cold water or lukewarm water until a target water contentand a target water activity are achieved, 2) in the case where ananimal- or plant-derived crude drug in the aqueous extract form isemployed, the relevant animal or plant material is extracted with wateror a water-ethanol mixture, and the resultant filtrate is concentratedwith the application of heat (25 to 50° C.) under reduced pressure untila target water content and a target water activity are achieved.

The capsule shells of the hard capsules according to the presentinvention are made of a base material containing a cellulose derivative.

Examples of the cellulose derivative include hydroxypropylmethylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carmelose, carboxymethylethylcellulose, cellulose acetate phthalate, and ethylcellulose. Inparticular, hydroxypropyl methylcellulose and methylcellulose arepreferred. The cellulose derivatives may be used singly or incombination of two or more species.

The cellulose derivative is incorporated in an amount of 15 to 30% byweight on the basis of the base material solution employed during theproduction of capsules. Also, additives which are generally employed inthe shape-imparting art, such as a gelling agent, a gelling aid, acolorant, a plasticizer, an emulsifier, a dispersant, and a preservativemay be added to the capsule base material.

Examples of the gelling agent to be employed include carrageenan,xanthan gum, locust bean gum, gellan gum, gum arabic, guar gum,tamarind-seed-derived polysaccharides, pectin, curdlan, gelatin,furcellaran, and agar. Preferably, carrageenan is employed. Thesematerials may be used singly or in combination of two or more species.The amount of the gelling agent to be added is 0.1 to 1.0% by weight onthe basis of the base material solution employed for the production ofcapsules.

Examples of the gelling aid to be employed include water-solublecompounds which release calcium ions, potassium ions, ammonium ions,sodium ions, or magnesium ions, and specific examples include calciumchloride, potassium chloride, ammonium chloride, ammonium acetate,potassium phosphate, potassium citrate, sodium chloride, magnesiumsulfate, and organic acids and water soluble salts thereof (for example,citric acid or sodium citrate). Water-soluble compounds providingpotassium ions or ammonium ions are preferably employed. The amount ofthe gelling aid to be added is 0.01 to 1.0% by weight on the basis ofthe base material solution employed for producing the capsules.

When a colorant is incorporated, any of ordinarily available additivesin the production of capsules may be used in suitable amounts. Examplesof the colorant include caramel, sodium copper chlorophyllin, riboflavinsodium phosphate, indigocarmine, Brilliant Blue, tartrazine, sunsetyellow, new coccine, amaranth, erythrosine, titanium oxides, and ironoxides. These colorants may be used singly or in combination of two ormore species.

Examples of the plasticizer include triethyl citrate, triacetin,glycerol, D-sorbitol, polyethylene glycol, acetylated monoglyceride,organic acids (e.g., citric acid, malic acid, and lactic acid), calciumcarbonate, and surfactants, and these plasticizers may be used singly orin combination of two or more species.

The hard capsules according to the present invention can be produced asfollows. As described above, the water content (w) and the wateractivity (a) of an internal solution are adjusted to 10<w≦80% and0.50≦a≦0.90, respectively, and the resultant solution is charged intothe aforementioned capsules by use of a conventional machine for fillingcapsules with a liquid-form drug designed to fill capsules with oilysubstances. Thereafter, in each capsule, the joint portion of thecapsule body and its corresponding cap is sealed with an aqueous ethanolsolution of a cellulose derivative, followed by drying in air.

Moreover, if necessary, the hard capsules of the present invention maybe coated with a coating agent, or with two or more coating agents incombination, containing, for example, hydroxypropyl methylcellulosephthalate, hydroxypropyl methylcellulose acetate succinate,carboxymethylethyl cellulose, cellulose acetate phthalate,polyvinylacetal diethylaminoacetate, or a methacrylate copolymer.

Packaging of the thus-produced capsules may be performed in anyconventional mode, by the use of, for example, bottles, aluminum foil,PTPs (press through packages), etc.

Preferred examples of the hard capsule of the present invention includethose having a property that the internal solution is a medicinal herbextract having a water content (w) of 30<w≦50% and a water activity (a)of 0.60≦a≦0.80, and the capsule shell contains hydroxypropylmethylcellulose, a gelling agent, and a gelling aid. In particular, acapsule which is #2 to #00 in capsule size and packed in bottles oraluminum pouches is preferred.

The present invention will next be described in more detail by way ofexamples, which should not be construed as limiting the inventionthereto.

EXAMPLE 1

An aqueous sodium chloride solution containing a ginseng extract wasprepared so that the water content was 74% or 78% and the water activitywas 0.80 or 0.83. The solution was placed in #0 capsules made ofhydroxypropyl methylcellulose, and the joining portion of the capsulebody and its corresponding cap was sealed with an aqueous ethanolsolution of hydroxypropyl methylcellulose, followed by drying in air.The resultant capsule samples were put in glass bottles, and stored at40° C. for one month. Whether there had been any leakage of the internalsolution from the hard capsules was visually checked. The results areshown in Table 1. Neither leakage of internal solution from the hardcapsules nor change of the capsule shape was observed. TABLE 1 Watercontent (%) 74 78 Water activity 0.80 0.83 Sodium chloride 0.30 0.26concentration (g/mL) 40° C., one month No liquid No liquid leakageleakage

EXAMPLE 2

An aqueous calcium chloride solution containing a ginseng extract wasprepared so that the water content was 67% or 70% and the water activitywas 0.75 or 0.78. The solution was placed in #0 capsules made ofhydroxypropyl methylcellulose. Subsequently, the capsule was sealed in amanner similar to that employed in Example 1, followed by drying in air.The resultant capsule samples were put in glass bottles, and stored at40° C. for one month. Whether there had been any leakage of the internalsolution from the hard capsules was visually checked. The results areshown in Table 2. Neither leakage of internal solution from the hardcapsules nor change of the capsule shape was observed. TABLE 2 Watercontent (%) 67 70 Water activity 0.75 0.78 Calcium chloride 0.41 0.37concentration (g/mL) 40° C., one month No liquid No liquid leakageleakage

EXAMPLE 3

An aqueous magnesium chloride solution containing a ginseng extract wasprepared so that the water content was 66% or 70% and the water activitywas 0.53 or 0.60. The solution was placed in #0 capsules made ofhydroxypropyl methylcellulose. Subsequently, the capsule was sealed in amanner similar to that employed in Example 1, followed by drying in air.The resultant capsule samples were put in glass bottles, and stored at40° C. for one month. Whether there had been any leakage of the internalsolution from the hard capsules was visually checked. The results areshown in Table 3. Neither leakage of internal solution from the hardcapsules nor change of the capsule shape was observed. TABLE 3 Watercontent (%) 66 70 Water activity 0.53 0.60 Magnesium chloride 0.45 0.40concentration (g/mL) 40° C., one month No liquid No liquid leakageleakage

COMPARATIVE EXAMPLE 1

An aqueous fructose glucose solution containing a ginseng extract wasprepared so that the water content was 40% or 50% and the water activitywas 0.85 or 0.88. The solution was placed in #0 capsules made ofhydroxypropyl methylcellulose. Subsequently, the capsule was sealed in amanner similar to that employed in Example 1, followed by drying in air.The resultant capsule samples were put in glass bottles, and stored at40° C. for one month. Whether there had been any leakage of the internalsolution from the hard capsules was visually checked. The results areshown in Table 4. In all samples, liquid leakage of internal solutionfrom the hard capsule was observed after storage for one week. TABLE 4Water content (%) 40 50 Water activity 0.85 0.88 40° C., one monthliquid liquid leakage leakage

1. A hard capsule filled with a solution containing an activeingredient, characterized in that the solution contains an inorganicchloride and has a water content (w) of 10<w≦80% and a water activity(a) of 0.50≦a≦0.90, and that the capsule is made of a base materialcontaining a cellulose derivative.
 2. A hard capsule as described inclaim 1, wherein the cellulose derivative is one or more membersselected from the group consisting of hydroxypropyl methylcellulose,methylcellulose, hydroxypropyl cellulose, and hydroxyethyl cellulose. 3.A hard capsule as described in claim 1 or 2, wherein the inorganicchloride is one or more members selected from the group consisting ofsodium chloride, magnesium chloride, and calcium chloride.
 4. A hardcapsule as described in any one of claims 1 to 3, wherein the activeingredient is selected from the group consisting of an aqueous extractof a medicinal herb, an aqueous extract of animal- or plant-origin, andan aqueous extract of fermented matter.